Determination of key structure-activity relationships in siRNA delivery with a mixed micelle system

作者：Pujol Marta Omedes; Coleman Daniel J L; Allen Christopher D; Heidenreich Olaf^*; Fulton David A

来源：Journal of Controlled Release, 2013, 172(3): 939-945.

DOI：10.1016/j.jconrel.2013.10.013

• siRNA
• Polymer micelles
• Leukaemia
• Structure-activity relationships
• Gene knockdown

Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure-activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions.

• 出版日期2013-12-28